Using dynamic combinatorial selection methods to identify chemical modifications of protein function

固有无序区(IDR)是一种普遍存在的蛋白质片段，不具有稳定的结构，是所有生物中发现的一类主要的蛋白质结构，预计存在于约三分之一的真核蛋白质中。至关重要的是，IDR在从癌症到蛋白质聚集障碍的关键信号和疾病途径中都是重要的和过度表达的。这个博士生将利用化学生物学方法来理解和操纵a-突触核蛋白的聚集行为--a-突触核蛋白是一种内在无序的蛋白质，在神经退行性疾病：帕金森病中发挥关键作用。我们将应用最先进的多肽和蛋白质化学、基于片段的配体发现方法以及先进的生物物理技术和结构方法来识别α-突触核蛋白序列的修饰，并系统地绘制其在体外和细胞内聚集行为的后果图。结果将建立一个平台，以确定国内流离失所者/国内流离失所者的调节者，并为描述聚集机制的新方法打开大门，这是一个至关重要的基本问题和推动药物发现的工具。

Intrinsically disordered regions (IDRs), are ubiquitous stretches of protein that do not adopt a stable structure, are a major class of protein structure found in all living organisms, and, are predicted to be present in around a third of eukaryotic proteins. Crucially, IDRs are important and overrepresented in key signalling and disease pathways, spanning cancer to disorders of protein aggregation.This PhD studentship will exploit chemical biology approaches to understand and manipulate the aggregation behaviour of a-synuclein - an intrinsically disordered protein which plays a key role in the neurodegenerative condition: Parkinson's disease. We will apply a state of the art combination of peptide and protein chemistry, fragment based ligand discovery methods and advanced biophysical techniques and structural methods to identify modifications to the sequence of a-synuclein and systematically map the consequences for its aggregation behaviour in vitro and in cells. The results will establish a platform to identify modulators of IDRs/IDPs and open the door to new methods to delineate aggregation mechanisms a basic question of critical importance and tools to drive drug-discovery.